Itch, or pruritus, is the unpleasant sensation that leads to a desire to scratch and is a common and distressing symptom in a variety of conditions and diseases. Itch also typically occurs in peripheral diseases such as allergic conjunctivitis, allergic rhinitis, hemorrhoids, and dermatoses of fungal, allergic and non-allergic origin, and in various inflammation-related diseases and disorders. Itching can also be a major symptom of many systemic diseases such as, Hodgkin's disease, chronic renal failure, polycythema vera, hyperthyroidism and cholestasis (see, for example, Herndon, J. H. Jr., Int. J. Derm. 14:465-484 (1975); Winkelmann, R. K., Med. Clins. N. Am. 66:1119-1133 (1982). In addition, senile itch is without an obvious cause, except perhaps xerosis, occurs in more than half of the population aged 70 years (Twycross et al., QJM. 2003, 96:7-26). In all cases chronic severe generalized itch can be disabling.
The sensation of itch is mediated by two distinct non-overlapping populations of cutaneous nerve fibers that evoke comparable degrees of itch (B. Namer et al., J. Neurophysiol. 100:2062-2069 (2008); L. M. Johanek et al., J. Neurosci. 28:7659-7669 (2008)). One set of fibers, the mechano-insensitive population, is more responsive to histamine than to cowhage. The other set is mechanosensitive and is more responsive to cowhage than to histamine (B. Namer et al.; L. M. Johanek et al., supra). Histamine is a classical mediator of itch and is associated with a wheal and flare. Since most clinical itches do not have a wheal or flare and do not respond to antihistamines, histamine is not thought to contribute to most itches (A. Ikoma et al., Nature Reviews Neurosci. 7, 535-547 (2006)). Cowhage refers to a tropical legume or, in this case, the loose hairs that cover the pods of Mucuna pruriens, and cowhage evoke itch. The active component of cowhage is mucunain, a cysteine protease that serves as a ligand for protease-activated receptors (PARs) 2 and 4 (V. B. Reddy et al., J. Neurosci. 28:4331-4335 (2008)).
Currently the standard treatment for itch is the administration of anti-histamines. However, not all forms of itch are responsive to anti-histamines. For example, cholestasis is characterized by generalized itch, which is not responsive to H1-antihistamines, indicating that histamine is probably not the major mediator involved. Approximately 25% of patients with uremia (chronic renal failure) suffer from severe itch unresponsive to H1-antihistamines or dialysis. However since histamine was believed to be the primary mediator of the itch sensation, conventional itch therapy involves H1-antihistamines as a first-line medication although antihistamines have no general anti-pruritic effect, and in many instances they are either ineffective or only partially effective.
Itching can be elicited by chemical, electrical, mechanical and thermal stimulation. So far no morphological structure has been identified as a specific receptor for the itch sensation, but it is assumed that itch receptors are linked to the free nerve endings of C-fibers close to the dermo-epidermal junction. The impulses set up in the thin, non-myelinated, slowly conducting C-fibers enter the spinal cord via the dorsal horn, then ascend in the contralateral spinothalmic tract, pass via the thalamus and end in the somatosensory cortex of the post-central gyrus. Itching and pain are related phenomena, and it was previously believed that itching was equal to sub-threshold pain, i.e. with increased activity in the C-fibers the perceived sensation changed from itching to pain. Although itch was once thought to be a subliminal form of pain (intensity theory), current evidence points to separate sensory neuronal systems mediating the two modalities. First, pain and itch are dissociable. Pain and itch evoke different motor responses, scratching for itch and withdrawal for pain. Second, based on clinical observations, systemically-administered opioids have a dichotomous effect on these two sensory modalities. μ-opioid receptor agonists reduce pain but can cause itch. Furthermore, antagonizing the central μ-opioid receptors, for example with naloxone or naltrexone, suppresses pruritus and at the same time may lower the pain threshold (Summerfield et al. Br. J. Dermatol. 1981, 105:725-6).
Clearly among all the topical and systemic agents that suppress itching in selected clinical settings there is no universally effective anti-pruritic drug. There is an urgent need for therapeutic agents for itch that do not target the histamine pathway. Such therapeutic agents would target non-histamine mediated itch.